CN1054586A - New substituted amine compound and preparation method thereof - Google Patents

New substituted amine compound and preparation method thereof Download PDF

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CN1054586A
CN1054586A CN91101218A CN91101218A CN1054586A CN 1054586 A CN1054586 A CN 1054586A CN 91101218 A CN91101218 A CN 91101218A CN 91101218 A CN91101218 A CN 91101218A CN 1054586 A CN1054586 A CN 1054586A
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compound
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rudimentary
salt
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盐川洋一
奥村和央
岳一彦
椿一典
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority claimed from GB909005247A external-priority patent/GB9005247D0/en
Priority claimed from GB909021806A external-priority patent/GB9021806D0/en
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Abstract

It is pharmaceutically acceptable with it that this paper introduces new substituted amine compound Salt and preparation method thereof, its structural formula as above: in the formula And R 1-6Definition referring to specification sheets, The compounds of this invention (1) and its pharmacy acceptable salt have anticholinergic activity and sodium channel blocking activity, can be used for treating human or animal's misnicturition or other disease.

Description

New substituted amine compound and preparation method thereof
The present invention relates to new substituted amine compound and medicine pharmacy acceptable salt thereof.
More particularly, the present invention relates to new substituted amine compound and pharmacy acceptable salt thereof, they have anticholinergic activity and sodium channel blocking activity, can be used for preventing and/or treating misnicturition, for example the pollakiuria that under situations such as neurotic pollakiuria, neurogenic bladder dysfunction, nycturia, unstable bladder, cystospasm, chronic bladder, chronic prostatitis, takes place, the urinary incontinence etc.; Prevent and/or treat the spasm and/or the hypanakinesia that under situations such as stomach ulcer, duodenal ulcer, hyperchlorhydria, esophagism, gastritis, enteritis, irritable colon syndrome, enterodynia, cholecystitis, cholangitis, pylorospasm, pancreatitis, take place, the pain that under situations such as the side effect of pancreatitis, bile dyskinesia, postcholecystectomy, urinary stone, urocystitis, dysmenorrhoea, perspire, urethrospasm, produces; Prevent and/or treat arrhythmia, congestive heart failure etc.; And as toponarcosis; And can expect and be used for preventing and/or treating asthma, paralysis agitans, stenocardia etc.; Also relate to the preparation method of described compound and salt thereof and comprise the medicinal compositions of this compound, and the method that prevents and/or treats the above-mentioned disease of human or animal.
One of purpose of the present invention provides new substituted amine compound and its pharmacy acceptable salt, and they can be used for preventing and/or treating above-mentioned disease.
Two of purpose of the present invention provides the method for the described substituted amine compound of preparation or its salt.
Three of purpose of the present invention provides and comprises as the described substituted amine compound of activeconstituents or the medicinal compositions of its pharmacy acceptable salt, can be used as the reagent that prevents and/or treats above-mentioned disease.
Four of purpose of the present invention provides the above-mentioned treatment of diseases method that prevents and/or treats.
The structural formula of substituted amine compound of the present invention (I) is as follows:
In the formula:
Formula Group be ring (rudimentary) alkyl or ring (rudimentary) alkenyl,
R 1And R 2The hydrogen of respectively doing for oneself, low alkyl group, ring (rudimentary) alkyl maybe can have one or more suitable substituent aryl,
R 3Be to have one or more suitable substituent low alkyl groups, can have one or more suitable substituent low-grade alkynyls and maybe can have one or more suitable substituent ring (rudimentary) alkyl,
R 4Be hydrogen, low alkyl group or aryl (rudimentary) alkyl, wherein
R 3And R 4Can be joined together to form and can have one or more suitable substituent heterocyclic groups,
R 5And R 6Respectively do for oneself hydrogen or hydroxyl,
But it is necessary
(ⅰ) work as formula
Figure 911012184_IMG32
Group is a cyclopentyl, R 1And R 2Respectively do for oneself and to have the phenyl of chlorine, R 5And R 6When respectively doing for oneself hydrogen, R 3Be the tertiary butyl,
(ⅱ) work as formula
Figure 911012184_IMG33
Group is a cyclohexyl, R 1And R 2The phenyl of respectively doing for oneself, R 5When being hydrogen, R 3Be the tertiary butyl,
(ⅲ) work as formula
Figure 911012184_IMG34
Group is a cyclohexenyl, R 1And R 2The phenyl of respectively doing for oneself, R 5And R 6When respectively doing for oneself hydrogen, R 3Be the tertiary butyl,
(ⅳ) work as formula
Figure 911012184_IMG35
Group is a cyclopentenyl, R ', R 2, R 5And R 6When respectively doing for oneself hydrogen, R 3It is the tertiary butyl.
Substituted amine compound of the present invention (I) can prepare by the method for each side shown in the following reaction scheme:
Figure 911012184_IMG36
In the formula:
Formula
Figure 911012184_IMG38
Group, R 1, R 2, R 3, R 4, R 5And R 6Definition the same,
Formula
Figure 911012184_IMG39
Group is ring (rudimentary) alkenyl,
Formula
Figure 911012184_IMG40
Group is ring (rudimentary) alkyl,
Formula Group is ring (rudimentary) alkyl or ring (rudimentary) alkenyl,
Formula R 7Compound be lower alkane ketone or lower alkanols alkanal, it can have one or more suitable substituting groups separately; Be rudimentary acetylenic ketone or rudimentary alkynes aldehyde, it can have one or more suitable substituting groups separately; Or can have one or more suitable substituent ring (rudimentary) alkane ketones,
X is a leavings group.
In the initial compounds, some compound (II) and (VI) are new, can be prepared by following reaction scheme:
Figure 911012184_IMG43
In the formula:
Ra 1And Ra 2The low alkyl group of respectively doing for oneself, ring (rudimentary) alkyl maybe can have one or more suitable substituent aryl,
R 8Be acyloxy,
R 9Be halogen,
X and formula
Figure 911012184_IMG44
The definition of group is the same,
Formula
Figure 911012184_IMG45
Group is ring (rudimentary) alkyl or cyclopentenyl.
Some initial compounds (IV) and (V) are new, can be by hereinafter method described in " preparation " or similar with it method make.
About substituted amine compound (I), it should be noted that compound (I) can comprise steric isomer owing to there is unsymmetrical carbon to exist.
The pharmaceutically-acceptable salts of suitable compounds (I) is conventional nontoxic single salt or disalt, comprising organic acid addition salt [for example formate, acetate, trifluoroacetate, maleate, tartrate, mesylate, benzene sulfonate, tosylate etc.], inorganic acid addition salt [for example hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt etc.], the salt that becomes with amino acid [for example arginic acid salt, aspartate, glutaminate etc.] etc.
In the context of the present specification, details are as follows for the suitable example of various definition:
Term " rudimentary " speech means 1 to 6 carbon atom (unless otherwise indicated).
" ring (rudimentary) alkyl " of suiting can comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl etc.Wherein preferably can be ring (C 3-C 6) alkyl, preferred can be cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Described " ring (rudimentary) alkyl " can have one or more (being preferably 1 pair 3) suitable substituting group, for example low alkyl group (for example: methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl etc.).
" ring (rudimentary) alkenyl " of suiting can comprise cyclopropenyl radical, cyclobutene base, cyclopentenyl, 2,4-cyclopentadienyl, cyclohexenyl, 1 base etc.Wherein preferably can be ring (C 5-C 6) alkenyl, preferred can be cyclopentenyl and cyclohexenyl.
" low alkyl group " that suits can comprise the alkyl of straight or branched, for example methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group and hexyl etc.Wherein preferably can be (C 1-C 4) alkyl, preferred can be methyl, ethyl, sec.-propyl, butyl and the tertiary butyl.
Described " low alkyl group " can have one or more (being preferably 1 to 3) suitable substituting group, for example hydroxyl; Aryl as mentioned below; N-(is rudimentary)-alkyl-N-aryl (rudimentary) alkylamino, wherein suitable " low alkyl group " part can be with reference to above-mentioned " low alkyl group ", and suitable " aryl (rudimentary) alkyl " part can be with reference to " aryl (rudimentary) alkyl " as mentioned below etc.; The specific examples of described " N-(is rudimentary) alkyl-N-aryl (rudimentary) alkylamino " can be N-methyl-N-benzyl amino, N-ethyl-N-benzyl amino, and N-propyl group-N-benzene ethylaminos etc. wherein preferably can be N-(C 1-4) alkyl-N-phenyl (C 1-4) alkylamino, preferred can be N-methyl-N-benzyl amino etc.
" low-grade alkynyl " that suits can comprise the alkynyl of straight or branched, for example ethynyl, 2-propynyl, 1-proyl, 2-butyne base, 2-methyl-3-butynyl, 3-pentynyl, 1, and 1-dimethyl-2-butyne base, 5-hexin base wherein preferably can be (C 2-C 6) alkynyl, preferred can be (C 4-6) alkynyl, most preferred can be 1,1-dimethyl-2-butyne base.
Described " low alkyl group " can have one or more (being preferably 1 to 3) suitable substituting group, N for example, N-two (rudimentary) alkylamino; Wherein suitable " low alkyl group " part can be with reference to above-mentioned " low alkyl group " etc.; Described N, the specific examples of N-two (rudimentary) alkylamino can be N, the N-dimethylamino, N-methyl-N-ethylamino, N, N-dipropyl amino, N-sec.-propyl-N-fourth amino, N, N-diamyl amino, N, N-two own amino etc. wherein preferably can be N, N-two (C 1-4) alkylamino, preferred can be N, the N-diethylin.
" aryl " that suit can comprise phenyl, naphthyl, and pentalene bases etc. wherein preferably can be phenyl.
Described " aryl " can have one or more (being preferably 1 to 3) suitable substituting group, for example above-mentioned low alkyl group etc.
" aryl (rudimentary) alkyl " that suits can comprise one-(or two-or three-) phenyl (rudimentary) alkyl, for example benzyl, styroyl, diphenyl-methyl, trityl etc.; Wherein preferably can be phenyl (rudimentary) alkyl, preferred can be phenyl (C 1-4) alkyl, most preferred can be benzyl.
R 3And R 4Suitable " heterocyclic group " when being joined together to form " heterocyclic group " can be to contain the N heterocyclic group.
" containing the N heterocyclic group " of suiting can comprise saturated or unsaturated, monocycle or polycyclic heterocyclic group for example contain unsaturated 3 to 8 yuan (being preferably 5 to 7 yuan) heteromonocyclic group groups of 1 to 4 nitrogen-atoms, and the example has: base (for example 1H-azepine)-1-base etc. the 1-azepine)), the 1-pyrryl, 1-pyrrolinyl, 1-imidazolyl, the 1-pyrazolyl, 1-pyridyl, 1-dihydropyridine base, the 1-pyrimidyl, pyrazinyl, 1-pyridazinyl, triazolyl (4H-1 for example, 2,4-triazole-4-base, 1H-1,2, the 3-triazol-1-yl, 2H-1,2,3-triazole-2-base etc.), tetrazyl (for example 1H-tetrazolium-1-base, 2H-tetrazolium-2-base etc.) etc.;
Contain saturated 3 to 8 yuan (being preferably 5 to 7 yuan) heteromonocyclic group groups of 1 to 4 nitrogen-atoms, the example has: the perhydro-azepine)-1-base (for example perhydro--carotene 1H-azepine)-1-base etc.), 1-pyrrolidyl, 1-imidazolidyl, piperidino-(1-position only), 1-piperazinyl etc.;
The unsaturated annelated heterocycles examples of groups that contains 1 to 4 nitrogen-atoms has: 1H-indoles-1-base, 2-pseudoindoyl, 1H-benzimidazolyl-, 1H-indazole-1-base, 2H-benzotriazole-2-base etc.;
The saturated annelated heterocycles examples of groups that contains 1 to 4 nitrogen-atoms has: 7-azabicyclo [2.2.1]-heptane-7-base, 3-azabicyclo [3.2.2] nonane-3-base etc.;
The example that contains unsaturated 3 to 8 yuan (being preferably 5 or 6 yuan) heteromonocyclic group groups of 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms has: 2, and 3-dihydro-oxazole-3-base etc.;
The example that contains saturated 3 to 8 yuan (being preferably 5 or 6 yuan) heteromonocyclic group groups of 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms has: morpholino, 3-full Qingization oxazolyl etc.;
The unsaturated annelated heterocycles examples of groups that contains 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms has: 2, and 3-Er hydrogen benzoxazole-3-base etc.;
The example that contains unsaturated 3 to 8 yuan (being preferably 5 or 6 yuan) heteromonocyclic group groups of 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms has: 2, and 3-dihydro-oxazole-3-base etc.;
Containing the example with saturated 3 to 8 yuan (being preferably 5 or 6 yuan) heteromonocyclic group groups 1 to 3 nitrogen-atoms 1 to 2 sulphur atom has: 1,3-thiazoles alkane-3-base etc.;
The unsaturated annelated heterocycles examples of groups that contains 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms has: 2, and 3-dihydro-benzothiazole-3-base etc.; Wherein preferably can be saturated 3 to the 8 yuan of heterocyclic groups that contain saturated 3 to 8 yuan of heteromonocyclic groups group of 1 to 4 nitrogen-atoms and contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, preferred can be 1-piperazinyl and morpholino.
Described " heterocyclic group " can have one or more (being preferably 1 to 3) suitable substituting group, for example lower alkane acyl group (for example formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl etc.) etc.
" the lower alkane ketone " that suits can comprise acetone, 2-butanone, 3-methyl-2-butanone, propione, methyl-n-butyl ketone etc.Wherein preferably can be (C 3-4) alkane ketone, preferred can be acetone.
" the lower alkanols alkanal " that suit can comprise formaldehyde, acetaldehyde, propionic aldehyde, butyraldehyde, 2 methyl propanal, valeral, hexanal etc.Wherein preferably can be (C 1-4) alkanal.
Described " lower alkane ketone " and " lower alkanols alkanal " can have one or more (being preferably 1 to 3) suitable substituting group, and for example hydroxyl, above-mentioned aryl, above-mentioned N-(are rudimentary) alkyl-N-aryl (rudimentary) alkylamino etc.
Described " rudimentary acetylenic ketone " can comprise 3-crotonylene-ketone, 3-pentyne-2-ketone, 3-methyl-4-pentyne-2-ketone, 5-hexane-3-ketone etc.Wherein preferably can be (C 4-6) acetylenic ketone.
Described " rudimentary alkynes aldehyde " can comprise propynal, 2-butyne aldehyde, 4-pentyne aldehyde, 2-methyl-3-tetrolic aldehyde, 4-hexin aldehyde etc.Wherein preferably can be (C 4-6) alkynes aldehyde.
Described " rudimentary acetylenic ketone " and " rudimentary alkynes aldehyde " can have one or more (being preferably 1 to 3) suitable substituting group, for example above-mentioned N, N-two (rudimentary) alkylamino etc.
What suit " encircles (rudimentary) alkane ketone and can comprise cyclopropanone, cyclobutanone, cyclopentanone, pimelinketone etc.Wherein preferably can be ring (C 3-6) alkane ketone.
Described " ring (rudimentary) alkane ketone " can have one or more (being preferably 1 to 3) suitable substituting group, for example above-mentioned low alkyl group etc.
" leavings group " that suits can comprise halogen (for example chlorine, fluorine, bromine, iodine); Acyloxy such as lower alkane acyloxy (for example acetoxyl group, propionyloxy, butyryl acyloxy, penta acyloxy, hexylyloxy etc.), sulfonyloxy (for example mesyloxy, ethanesulfonyloxy group, tosyloxy etc.) etc.
In substituted amine compound of the present invention (I), a kind of preferred compound can be represented by formula (I-1):
Figure 911012184_IMG46
In the formula:
R 1, R 2, R 3And R 4Definition the same, wherein preferred R 1And R 2Can be separately and have one or more substituent aryl, preferred can respectively doing for oneself has the phenyl of 1 to 3 low alkyl group, the most preferred phenyl of can respectively doing for oneself; Preferred R 3Can be to have one or more suitable substituent low alkyl groups, preferred can be low alkyl group, most preferably can be the tertiary butyl; Preferred R 4Can be hydrogen and low alkyl group, preferred can be hydrogen.
Another preferred compound in the substituted amine compound of the present invention (I) can be represented by formula (I-2):
Another preferred compound in the substituted amine compound of the present invention (I) can be represented by formula (I-3):
Figure 911012184_IMG48
In the formula:
R 1, R 2, R 3And R 4Definition the same, wherein preferred R 1And R 2Can be separately and have one or more suitable substituent aryl, preferred can be the phenyl with 1 to 3 low alkyl group, and most preferred can be phenyl; Preferred R 3Can be to have one or more suitable substituent low alkyl groups, preferred can be low alkyl group, and most preferred can be methyl, sec.-propyl and the tertiary butyl; Preferred R 4Can be hydrogen and low alkyl group, preferred can be hydrogen and ethyl.
It should be noted that the only explanation as an example of preferred compound of some above-mentioned substituted amine compounds of the present invention (I) hereinbefore, thereby the scope of substituted amine compound of the present invention (I) never is limited to above-mentioned preferred embodiment.
Details are as follows to prepare the method for The compounds of this invention (I).
Method 1
The compounds of this invention (I) or its salt can prepare as follows, that is, and and with compound (II) and compound (III) or its reactant salt.
The suitable salt of compound (III) can be the salt that compound (I) is enumerated.
This reaction can be implemented in following solvents: for example water, phosphate buffered saline buffer, acetone, chloroform, acetonitrile, oil of mirbane, methylene dichloride, ethylene dichloride, methane amide, N, dinethylformamide, methyl alcohol, ethanol, diethyl ether, tetrahydrofuran (THF), methyl-sulphoxide perhaps preferably have in the strong polar organic solvent and are implementing reacting other harmless organic solvent.Wherein, hydrophilic solvent can mix use with water.
This reaction is preferably under the alkali existence to be carried out, for example mineral alkali (for example alkalimetal oxide, alkaline carbonate, alkali metal hydrocarbonate) and organic bases (for example trialkylamine) etc.
It is not strict that temperature of reaction is handed over, and reacts under room temperature, warm or heating usually.
This reaction is preferably in alkali metal halide (for example sodium iodide, potassiumiodide etc.), alkali metal thiocyanate (for example Sodium Thiocyanate 99, potassium sulfocyanate etc.) etc.
Should react, during reaction, available ordinary method reactions such as (for example with) methylsulfonyl chlorides transforms and obtains compound (II) from corresponding alkylol cpd.
For this method, it should be noted that:
Formula when compound (II) Group is ring (rudimentary) alkenyl and leavings group X when being positioned at the allyl group position of two keys, during situation in the promptly following formula:
Figure 911012184_IMG50
The situation that may exist is that compound (III) reacts in (3) position rather than in (1) position, and this situation is also included within the scope of the present invention.
Method 2
The compounds of this invention (I) or its salt can prepare as follows,, earlier with compound (IV) and compound (III) or its reactant salt, make the midbody compound reduction that obtains then that is.
This reaction can not separate midbody compound and directly carries out.
ⅰ) reaction of compound (IV) and compound (III) or its salt is carried out in conventional solvent usually, and for example alcohol (for example methyl alcohol, ethanol), methylene dichloride, chloroform are perhaps carrying out reacting in harmless other solvent.
Temperature of reaction is not strict, can be under cooling, room temperature, be warmed under the heating and react.
ⅱ) this reduction reaction is performed as follows, promptly with reductive agent reaction, for example: and metal hydride, as alkali metal aluminum (for example lithium aluminum hydride etc.); Hydrogenation two (rudimentary) aluminum alkyls (for example diisobutylaluminium hydride etc.); Alkali metal borohydride (for example sodium borohydride etc.) etc.
This reaction is carried out in solvent usually, diethyl ether for example, and chloroform, methylene dichloride, tetrahydrofuran (THF), benzene, toluene, alcohol (for example methyl alcohol, ethanol etc.) is perhaps carrying out reacting in harmless other solvent.
Temperature of reaction is not strict, can the cooling under, room temperature or warm under react.
When compound (IV)
Figure 911012184_IMG51
When group was ring (rudimentary) alkenyl, the situation that may exist was that two keys of described ring (rudimentary) alkenyl also are reduced into singly-bound between reduction period, and this situation is also included within the scope of the present invention.
Method 3
(I a) or the reduction of its salt can make compound of the present invention (I b) or its salt to make compound.
Suitable compounds (I a) and the salt of (I b) can be as the cited salt of compound (I).
Method of reducing can comprise catalytic reduction etc.
The suitable catalyzer that is used for catalytic reduction is a conventional catalyst, platinum catalyst (for example platinized platinum, platinum sponge, platinum black, colloidal state platinum, platinum oxide and platinum filament etc.) for example, palladium catalyst (for example palladium suede, palladium black, palladous oxide, palladium-carbon, pallamine, palladium-barium sulfate, palladium-barium carbonate etc.), nickel catalyzator (for example reduced nickel, nickel oxide and Raney nickel etc.), cobalt catalyst (for example reduce cobalt, Raney cobalt etc.), iron catalyst (for example reduced iron, the interior iron of Ruan etc.), copper catalyst (for example going back copper, Ullman copper etc. in native copper, the Ruan) etc.
Reduction reaction is being implemented reacting in the harmless conventional solvent usually, for example water, methyl alcohol, ethanol, propyl alcohol, N, dinethylformamide, ethyl acetate, diethyl ether, diox, tetrahydrofuran (THF) or its mixture.
The temperature of reaction of this reduction reaction is not strict, carries out under warm being cooled to usually.
Method 4
The compounds of this invention (I c) or its salt can be made by compound (V) and compound (III) or its reactant salt.
The salt of suitable compounds (I c) can be as the cited salt of compound (I).
Can carry out this step reaction by the similar approach of method 1.
Method 5
The compounds of this invention (I c) or its salt can be made through the glycol elimination reaction by compound (I d) or its salt.
The salt of suitable compounds (I d) and (I e) can be as the cited salt of compound (I).
The elimination reaction of this method can be implemented as follows, that is, compound (I d) or its salt earlier with aldehyde cpd (for example phenyl aldehyde etc.), orthoformic acid three (rudimentary) alkyl ester (for example formic acid trimethyl etc.) reaction, then with alkali or and acid-respons.Described alkali is low alkyl group lithium (for example lithium methide, n-Butyl Lithium etc.), two (rudimentary) alkyl lithamide (for example di-isopropyl lithamide etc.) and alkali metal hydroxide (for example sodium hydroxide etc.) etc. for example.Described acid is lower alkanols alkanoic acid (for example acetate, propionic acid etc.), sulfonic acid (for example tosic acid etc.) for example.
This reaction is carried out in solvent usually, and for example normal hexane, diethyl ether, tetrahydrofuran (THF), methylene dichloride, toluene, dimethylbenzene are perhaps reacting reacting in harmless other solvent.
Temperature of reaction is not strict, can be in room temperature, be warmed under the heating and react.
Method 6
The compounds of this invention (I f) or its salt can prepare as follows, that is, compound (VI) or its salt react with phosphine compound and compound (VII) earlier, then with resultant midbody compound reduction.
The salt of suitable compounds (I f) and (VI) can be the salt cited as chemical compounds I.
" phosphine compound " that suit can comprise triphenyl phosphine etc.
ⅰ) reaction of compound (VI) or its salt and phosphine compound and compound (VII) can be implemented in solvent usually, and for example diethyl ether, tetrahydrofuran (THF) are perhaps carrying out reacting in harmless other solvent.When compound (VII) when being liquid, also can be used as solvent.
Temperature of reaction is not strict, can be in room temperature, be warmed under the heating and react.
ⅱ) reduction reaction of this method can be implemented by the similar approach of method 2.
Details are as follows for the preparation method of some initial compounds (II) and (VI):
Method A
Step 1
Compound (VIII) reduction can be made compound (IX).
The reduction reaction of this step can be implemented by the similar approach of method 2.
Step 2
Compound (IX) acidylate can be made compound, and (II a).
The acylation reaction of this step can be implemented as follows, that is, and and compound (IX) and acid or its reactive derivative or its reactant salt of waiting to introduce corresponding acyl group.
This reaction can be implemented (method of partly being introduced as this specification sheets " preparation ") by the ordinary method of this area.
Step 3
Compound (IX) halogenation can be made compound (II b).
The halogenating reaction of this step can be implemented as follows, that is, and and reactions such as compound (IX) and carbon tetrahalide (for example tetracol phenixin, carbon tetrabromide etc.), thionyl halide (for example thionyl chloride etc.).
This reaction can be implemented (method of partly being introduced as this specification sheets " preparation ") by the ordinary method of this area.
Method B
Compound (II c) can be made compound through the azido-substitution reaction, and (VI a) or its salt.
The substitution reaction of this method can be implemented as follows, that is, and and reactions such as compound (II c) and triazo-compound such as an alkali metal azide (for example sodiumazide etc.).
This reaction can be implemented (method of partly being introduced as " preparation " of this specification sheets) by the ordinary method of this area.
The compounds of this invention (I) and its pharmacy acceptable salt have anticholinergic activity and sodium channel blocking activity, can be used for treating misnicturition or other disease of foregoing humans and animals.
Take The compounds of this invention (I) and its pharmacy acceptable salt, can alleviate for example platycoria etc. of side effect.
Be the purposes of explanation The compounds of this invention (I) and its pharmacy acceptable salt, hereinafter enumerated the pharmacological test data of representation compound of the present invention.
Mouse fed to appetite water brought out contain the inhibition test of urinating bladder contracts
[I] test method
Choose the male mouse of Sprague-Dawly of several body weight 240-250g, use urethanum (1.0g/kg body weight) fiber crops alcohol, cut open the belly from the belly center line and expose bladder, the record intravesical pressure; To be connected in the little otch insertion intravesical of the globe of stainless steel tube (external diameter 1.2mm, a long 5cm) end by the bladder top, the other end of this pipe is connected to sensator.Ligation and incision ureter are putting polyethylene tube to external urethral catheterization near cut ends.
Contain urine bladder hyperactivity hyperkinesia (forcing the hyperdynamia contracture) because the bladder water-filling brings out, therefore, intravesical globe is full of the water that produces the about 10mm mercury column of surplus pressure.Detect the systemic blood pressure and the rhythm of the heart from the neck aorta of mouse.
When being tending towards constant because of the water-filling contracture, with test compound in the mouse body is gone in intravenous injection.
[II] test compound
(1)-and the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine mesylate
[III] test-results
ED 30＝0.18mg/kg
The activity test of Na channel blocking
[I] test method:
Male white rabbit is planted by the Japan that chooses several body weight 2.0-3.0kg, the toponarcosis effect of evaluation test compound corneal opticofacial winking reflex.A soft monofilament (palpus of rabbit) is adjacent to cornea, bring out corneal reflex, eyes are used the salt brine solution (50 μ l splash into) of 1.0% test compound, the another eyes in contrast, record cornea moment reaction 5,15 minutes time the after using test compound.
The toponarcosis activity is with the inhibition percentage expression of moment reaction.
[II] test compound
(1)-and the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
[III] test-results
Suppress %
5 minutes 100
15 minutes 100
Medicinal compositions of the present invention can be used with pharmaceutical dosage forms, for example is solid, semisolid or liquid form.Wherein contain The compounds of this invention (I) as activeconstituents or its pharmacy acceptable salt and organic or inorganic carrier or and mixed with excipients, be applicable to that rectum, lung (nose or oral cavity suck), nose, eye are with, external application (surface), oral or non-enteron aisle (comprising subcutaneous, intravenously and intramuscular) administration, perhaps suction or intravesical administration.
Activeconstituents can be mixed and made into tablet, pill, lozenge, capsule, suppository, butterfat, ointment, aerosol, suction pulvis, solution, emulsion, suspension and other form that is suitable for using with for example nontoxic pharmaceutically acceptable carrier commonly used.In addition, can add assistant agent, stablizer, stiff agent and tinting material and spices in case of necessity.The amount of the The compounds of this invention that comprises in pharmaceutical composition (I) or its pharmaceutically-acceptable salts is enough to produce desired effect to illness.
With regard to compound to regard to human or animal's the route of administration, preferably by vein, intramuscular, lung or oral administration or inhalation.The dosage of the treatment significant quantity of The compounds of this invention (I) changes with each concrete patient's age to be treated and illness.In general, prevent and treat above-mentioned disease given dosage: the intravenous injection per daily dose is a per kilogram human or animal body weight 0.01-20mg The compounds of this invention (I), the intramuscularly per daily dose is a per kilogram human or animal body weight 0.1-20mg The compounds of this invention (I), and oral per daily dose is a per kilogram human or animal body weight 0.5-50mg The compounds of this invention (I).
Following preparation and embodiment are intended to be described in more detail the present invention.
Preparation 1
Under 0 ℃ to 3 ℃, sodium borohydride (0.16g) ethanol (6ml) solution is splashed into 5, in the methyl alcohol (10ml) of 5-phenylbenzene-2-cyclopentenes-1-ketone (1.0g), cerous compounds heptahydrate (1.59g) and methylene dichloride (4ml) solution.In 1 hour, cerous compounds heptahydrate (0.80g) and sodium borohydride (0.08g) branch are added in the reaction mixture for 4 times, after finishing, reaction adds cold water (30ml), this mixture chloroform extraction.Extracting solution salt water washing is used dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, uses the methylene dichloride wash-out, gets 5,5-phenylbenzene-2-cyclopentenes-1-alcohol (0.83g).
IR（Neat）：3550，3420cm -1
NMR(CDCl 3, δ): 1.28(1H, broadband s), 2.82-3.00(1H, m), 3.40-3.55(1H, m), 5.45(1H, s), 5.88-5.98(1H, m),
6.08-6.20（1H，m），7.10-7.40（10H，m）
Embodiment 1
Under 5 ℃ to 10 ℃, methylsulfonyl chloride (0.35ml) and triethylamine (0.60ml) are added 5, the N of 5-phenylbenzene-2-cyclopentenes-1-alcohol (0.20g), in dinethylformamide (1ml) solution, stir after 1 hour, under 5 to 12 ℃, TERTIARY BUTYL AMINE (1.78ml) is added in this reaction mixture, in stirring at room 3 days.In reaction mixture, add entry and ethyl acetate, isolate organic layer, wash with water, use dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture wash-out, gets the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (0.11g).
NMR(CDCl 3, δ): 0.80-1.40(1H, broadband m), 1.12(9H, s), 2.04(1H, dd, J=7.6Hz and 13.0Hz), 3.09(1H, dd, J=6.8Hz and 13.0Hz), 3.94-4.10(1H, m), 5.35(1H, dd, J=1.7Hz and 5.6Hz), 6.21(1H, dd, J=2.0Hz and 5.6Hz), 7.09-7.38(10H, m)
Embodiment 2
Corresponding unhindered amina compound by embodiment 1 can make the N-tertiary butyl-4 according to a conventional method, 4-phenylbenzene-2-cyclopentamine mesylate.
mp：204-206℃
IR（Nujol）：1600，1490cm -1
NMR(DMSO-d 6, δ): 1.42(9H, s), 2.50(3H, s), 2.79(1H, dd, J=13.1Hz and 8.9Hz), 3.23(1H, dd, J=13.1Hz and 6.7Hz), 4.18-4.34(1H, m), 6.22(1H, dd, J=5.7Hz and 1.2Hz), 6.36(1H, dd, J=5.7Hz and 2.1Hz), 7.08-7.35(10H, m), 8.67(2H, broadband s)
Embodiment 3
With (±)-N-tertiary butyl-4, ethanol (30ml) solution of 4-phenylbenzene-2-cyclopentamine (17.22g) and (-)-two toluoyls-L-tartrate (11.69g) refluxes, and gained solution leaves standstill in room temperature.After keeping leaving standstill 8 hours, collect the throw out that generates, with ethanol recrystallization repeatedly, (+)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine 1/2[(-)-two toluoyls-L-tartrate] (4.15g).Gained salt is added in 10% aqueous sodium hydroxide solution, extracts with diethyl ether.Extracting solution salt water washing is used dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture (20: 1) wash-out, gets (+)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (1.58g).
[α] 30 D＝+172.24（C＝1.39，MeOH）
IR（Film）：3310，3050，1595cm -1
NMR(CDCl 3, δ): 0.60-1.60(1H, broadband m), 1.13(9H, s), 2.04(1H, dd, J=13.0Hz and 7.7Hz), 3.09(1H, dd, J=13.0Hz and 6.8Hz), 4.04(1H, dddd, J=7.7Hz, 6.8Hz, 2.0Hz a 1.7Hz), 5.86(1H, dd, J=5.5Hz and 1.7Hz), 6.21(1H, dd, J=5.5Hz and 2.0Hz), 7.09-7.47(10H, m)
Embodiment 4
Ready-formed (+)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine; 1/2[(-)-two toluoyls-L-tartrate] mother liquor by being converted into corresponding amine (9.44g) with aqueous sodium hydroxide solution reaction.Add (+)-two toluoyls-D-tartrate (6.50g) and ethanol (25ml) in the amine that obtains (9.44g), this mixture reflux is until obtaining settled solution.After the room temperature standing over night, the throw out that filter to collect generates, with ethanol recrystallization repeatedly, (-)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine 1/2[(+)-two toluoyls-D-tartrate] (6.90g).
IR（Nujol）：1720，1635cm -1
NMR（DMSO-d 6，δ）：1.18（18H，s），
2.24(2H, dd, J=13.2Hz and 8.4Hz), 2.35(6H, s), 3.19(2H, dd, J=13.2Hz and 6.9Hz), 4.18(2H, broadband t, J=7.4Hz), 5.58(2H, s), 5.92(2H, d, J=5.5Hz), 6.37(2H, d, J=5.5Hz), 7.07-7.38(24H, m), 7.84(4H, d, J=8.1Hz)
Embodiment 5
With (-)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine 1/2[(+)-two toluoyls-D-tartrate] (6.36g) be added in 10% aqueous sodium hydroxide solution, extract with diethyl ether.Dried over mgso is used in extracting solution salt water washing, and vacuum-evaporation gets (-)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (3.54g).
IR（Film）：3310，3050，1595cm -1
NMR(CDCl 3, δ): 0.60-1.60(1H, broadband m), 1.13(9H, s), 2.04(1H, dd, J=13.0Hz and 7.7Hz), 3.09(1H, dd, J=13.0Hz and 6.8Hz), 4.03(1H, dddd, J=7.7Hz, 6.8Hz, 2.0Hz and 1.7Hz), 5.85(1H, dd, J=5.5Hz and 1.7Hz), 6.21(1H, dd, J=5.5Hz and 2.0Hz), 7.09-7.47(10H, m)
Embodiment 6
Ethyl acetate (1ml) solution of methylsulfonic acid (1.16g) is added to (-)-N-tertiary butyl-4, and in ethyl acetate (20ml) solution of 4-phenylbenzene-2-cyclopentamine (3.54g), vacuum evaporating solvent also adds diethyl ether.After leaving standstill 4 hours, filter and collect the throw out that generates, get (-)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine mesylate (3.90g).
[α] 28 D＝-155.64°（C＝1.05，MeOH）
mp：150-151℃
IR（Nujol）：3400，1600cm -1
NMR(CDCl 3, δ): 1.43(9H, s), 2.51(3H, s), 2.79(1H, dd, J=13.1Hz and 8.9Hz), 3.24(1H, dd, J=13.1Hz and 6.7Hz), 4.28(1H, broadband t, J=8.1Hz), 6.22(1H, d, J=5.7Hz), 6.36(1H, dd, J=5.7Hz and 2.1Hz), 7.08-7.35(10H, m), 8.31-8.87(2H, broadband m)
Embodiment 7
Similar approach by embodiment 6 can make (+)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine mesylate.
[α] 29 D＝+155.84°（C＝0.817，MeOH）
mp：153-154℃
IR（Nujol）：3400，1600cm -1
NMR(CDCl 3, δ): 1.42(9H, s), 2.51(3H, s), 2.79(1H, dd, J=13.1Hz a 8.9Hz), 3.24(1H, dd, J=13.1Hz and 6.7Hz), 4.28(1H, broadband t, J=8.1Hz), 6.22(1H, d, J=5.7Hz), 6.37(1H, dd, J=5.7Hz and 2.0Hz), 7.08-7.35(10H, m), 8.08-9.27(2H, broadband)
Embodiment 8
2N aqueous sodium hydroxide solution (10ml) is added to (-)-N-tertiary butyl-4, in the ethyl acetate suspension of 4-phenylbenzene-2-cyclopentamine mesylate (0.70g), separates organic layer.The salt water washing of this solution by 10% palladium-carbon (0.06g) hydrogenation, gets (-)-N-tertiary butyl-3,3-phenylbenzene cyclopentamine (0.53g).The methanol solution of methylsulfonic acid (174mg) is added to (-)-N-tertiary butyl-3, in the chloroformic solution of 3-phenylbenzene cyclopentamine (0.53g), vacuum evaporating solvent is developed with diethyl ether, get (-)-N-tertiary butyl-3,3-phenylbenzene cyclopentamine mesylate (0.63g).
[α] 23 D＝-4.75°（C＝0.40，CH 3OH）
mp：178℃
NMR(CDCl 3, δ): 1.37(9H, s), 2.00-2.70(5H, m), 2.65(3H, s), 3.10-3.28(1H, m), 3.38-3.58(1H, m), 7.05-7.30(10H, m), 8.43(2H, broadband s)
Embodiment 9
Similar approach by embodiment 8 can make (+)-N-tertiary butyl-3,3-phenylbenzene cyclopentamine mesylate.
[α] 23 D＝+4.60°（C＝1.0，MeOH）
mp：178℃
NMR(CDCl 3, δ): 1.37(9H, s), 2.00-2.70(5H, m), 2.65(3H, s), 3.10-3.28(1H, m), 3.38-3.58(1H, m), 7.05-7.30(10H, m), 8.43(2H, broadband s)
Embodiment 10
Under 0-10 ℃, water (15ml) and concentrated hydrochloric acid (5ml) are added to (-)-N-tertiary butyl-4, stirred 30 minutes in diethyl ether (50ml) solution of 4-phenylbenzene-2-cyclopentamine (8.82g), filter and collect the throw out that generates, wash with diethyl ether, get (-)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride (9.70g).
[α] 26 D＝-189.4°（C＝1.073，CH 3OH）
Mp:259-261 ℃ (decomposition .)
IR（Nujol）：2730，2690，2640，2610，2475，2440cm -1
NMR(CDCl 3, δ): 1.47(9H, s), 3.10(1H, dd, J=8.5 and 13.1Hz), 3.17(1H, dd, J=7.4 and 13.1Hz), 4.23(1H, broadband s), 6.16(1H, dd, J=5.7 and 2.3Hz), 6.41(1H, dd, J=5.7 and 1.4Hz), 7.04-7.41(10H, m), 9.64(1H, broadband s), 9.75(1H, broadband s)
Preparation 2
Under-78 ℃ to-50 ℃, in 10 minutes with diisobutylaluminium hydride (15ml, 1.5M be dissolved in the solution of toluene) splash into 5, in toluene (25ml) suspension of 5-phenylbenzene-2-cyclopentenes-1-ketone (5.0g), after 30 minutes, ethyl acetate (5ml) is added in the yellow solution of generation, adds 6N hydrochloric acid (20ml) again and make this solution be acidified to pH1, use ethyl acetate extraction.Extracting solution salt water washing is used dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, uses the methylene dichloride wash-out, to further purification of ball distillation, obtains 5,5-phenylbenzene-2-cyclopentenes-1-alcohol (2.46g) through ball.
bp：200℃/0.4mmHg
The physical data of this compound is identical with preparation 1 compound.
Preparation 3
Under the room temperature, the 4-Dimethylamino pyridine of acetic anhydride (0.84ml) and catalytic amount is added to 5, in pyridine (5ml) solution of 5-phenylbenzene-2-cyclopentenes-1-alcohol (0.70g), stirs after 30 minutes, add dilute hydrochloric acid and make the pH value of reaction mixture transfer to 1.0, use ethyl acetate extraction.Dried over mgso is used in extracting solution salt water washing, and vacuum-evaporation obtains acetate 5,5-phenylbenzene-2-cyclopentenes ester (0.82g).
IR（Neat）：1720cm -1
NMR（CDCl 3，δ）：1.68（3H，s），2.80-3.00（1H，m），3.48-3.70（1H，m），6.00-6.10（1H，m），6.14-6.26（1H，m），6.49（1H，s），7.10-7.35（10H，m）
Preparation 4
With acetate 5, the mixture of 5-phenylbenzene-2-cyclopentenes ester (0.30g) and sodiumazide (84mg) is dissolved in the solution of tetrahydrofuran (THF) (3ml) and water (1.5ml), under argon atmospher and room temperature, adds four (triphenyl phosphine) palladium (0) (62mg).Stir after 14.5 hours, add ethyl acetate, isolate organic layer, use the salt water washing, use dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, and the mixture wash-out with normal hexane and ethyl acetate obtains 4,4-phenylbenzene-2-cyclopentenyl nitrine (0.16g).
IR（Neat）：2100cm -1
NMR(CDCl 3, δ): 2.45(1H, dd, J=6Hz and 14Hz), 3.05(1H, dd, J=14Hz and 8Hz), 4.42-4.70(1H, m), 5.90(1H, dd, J=2Hz and 6Hz), 6.42(1H, dd, J=1Hz and 6Hz), 6.95-7.30(10H, m)
Preparation 5
Under the room temperature, (100ml) splashes into 2 with 50% aqueous sodium hydroxide solution, in the mixture of 2-diphenylacetonitrile (135.77g), 2-propynyl chlorine (52.35g) and hydrogen sulfate first fourth ammonium (0.51g).Stir after 6 hours, this mixture is poured in the water, extract with diethyl ether.This extracting solution is used dilute hydrochloric acid and salt water washing successively, vacuum-evaporation, residue vacuum distilling obtains 2,2-phenylbenzene-2-(2-proyl) acetonitrile.
bp：138-142℃（0.3mmHg）
IR（Film）：3290，3060，2240，1600cm -1
NMR（CDCl 3，δ）：2.13（1H，t，J＝2.6Hz），3.25（2H，d，J＝2.6Hz），7.22-7.53（10H，m）
Preparation 6
With 2,2-phenylbenzene-2-(2-proyl) tetrahydrofuran (THF) (15ml) solution of acetonitrile (1.38g) and lithium aluminum hydride (0.21g) refluxed 2 hours, and reaction mixture is poured in the cold water, added hcl acidifying, extracted with diethyl ether.Extracting solution salt water washing is used dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, and mixture (1: the 1) wash-out with normal hexane and benzene obtains 2,2-phenylbenzene-2(2-proyl) acetaldehyde (0.46g).
IR（Film）：3280，3050，1715，1595cm -1
NMR（CDCl 3，δ）：1.92（1H，t，J＝2.7Hz），3.15（2H，d，J＝2.7Hz），7.16-7.54（10H，m），9.85（1H，s）
Preparation 7
Mercuric acetate (3.1g) and sulfuric acid (18.3g) are dissolved in the mixture of acetate (300ml) and water (75ml), under the room temperature toward wherein splashing into 2,2-phenylbenzene-2-(2-proyl) acetate (83ml) solution of acetaldehyde (83.0g), dripped off in two hours, reaction mixture is poured in the water, extracted with diethyl ether.Extracting solution is water and sodium bicarbonate aqueous solution washing successively, vacuum-evaporation.Residue is purified through silica gel column chromatography, and mixture (5: the 1) wash-out with normal hexane and ethyl acetate obtains 3-ethanoyl-2,2-phenylbenzene propionic aldehyde (48.9g).
IR（Film）：3060，1720，1600cm -1
NMR（CDCl 3，δ）：2.05（3H，s），3.59（2H，s），7.14-7.45（10H，m），10.02（1H，s）
Preparation 8
With 3-ethanoyl-2,2-phenylbenzene propionic aldehyde (48.9g) is dissolved in the mixture of tetrahydrofuran (THF) (55ml) and methyl alcohol (30ml), adds 10% potassium hydroxide aqueous solution (15ml), this solution stirring 2 hours, vacuum-evaporation under the room temperature.Add salt solution to residue, extract with diethyl ether.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue is purified through silica gel column chromatography, and mixture (5: the 1) wash-out with normal hexane and ethyl acetate obtains 4,4-phenylbenzene-2-cyclopentenes-1-ketone (39.76g).
IR（Film）：3080，1700，1665，1580cm -1
NMR（CDCl 3，δ）：3.12（2H，s），6.25（1H，d，J＝5.6Hz），7.06-7.49（10H，m），7.99（1H，d，J＝5.6Hz）
Preparation 9
At-5 ℃ under 4 ℃, normal hexane (2.0ml) solution of 1M diisobutylaluminium hydride is added to 4, in toluene (3ml) solution of 4-phenylbenzene-2-cyclopentenes-1-ketone (0.30g), stir after 20 minutes, add ethyl acetate (3ml) and 10% hydrochloric acid (2ml) successively, this mixture ethyl acetate extraction.Mention liquid salt water washing, use dried over sodium sulfate, vacuum-evaporation.Residue is purified through silica gel column chromatography, uses the methylene dichloride wash-out, obtains 4,4-phenylbenzene-2-cyclopentenes-1-alcohol (0.29g).
IR（Neat）：3320cm -1
NMR(CDCl 3, δ): 2.41(1H, dd, J=4.7Hz and 13.8Hz), 3.00(1H, dd, J=6.9Hz and 13.8Hz), 4.90-5.10(1H, m), 5.98(1H, dd, J=2.0Hz and 5.5Hz), 6.38(1H, dd, J=1.2Hz and 5.5Hz), 7.1-7.38(10H, m)
Preparation 10
With 2, two (p-methylphenyl) acetate (8.52g) of 2-, vinyl carbinol (6.6ml) and tosic acid-hydrate (0.34g) refluxed 20 hours with the mixture of toluene (25ml), removed moisture content continuously with Dean Rodney Stark device.After the cooling, this mixture is poured in the 1N aqueous sodium hydroxide solution, used ethyl acetate extraction.Extracting solution is used dried over mgso, vacuum-evaporation with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid and salt water washing.Residue is purified through silica gel column chromatography, uses the methylene dichloride wash-out, obtains 2, two (p-methylphenyl) allyl acetates (8.09g) of 2-.
IR（Film）：1730，770，750cm -1
NMR（CDCl 3，δ）：2.31（6H，s），4.60-4.70（2H，m），4.98（1H，s），5.15-5.30（2H，m），5.80-6.00（1H，m），6.95-7.36（8H，m）
Preparation 11
Under 130 ℃, nitrogen atmosphere, with 2, toluene (40ml) solution of two (p-methylphenyl) allyl acetates (8.00g) of 2-splashes into sodium hydride (60%, be scattered in the mineral oil) in (1.6g) toluene (30ml) suspension, this mixture refluxed 6 hours, pour into after the cooling in the cold 1N hydrochloric acid, use ethyl acetate extraction.Dried over mgso is used in extracting solution salt water washing, and vacuum-evaporation obtains 2, two (the p-methylphenyl)-4-pentenoic acids (4.41g) of 2-, and it need not further purification, can be directly used in next reaction.
NMR（CDCl 3，δ）：2.32（6H，s），3.12（2H，d，J＝6.9Hz），4.89（1H，s），4.96（1H，d，J＝5.1Hz），5.45-5.70（1H，m），6.90-7.25（8H，m）
Preparation 12
(3.2ml) is added to 2 with thionyl chloride, the N of two (the p-methylphenyl)-4-pentenoic acids (8.17g) of 2-, and in dinethylformamide (1.0ml) and methylene dichloride (45ml) solution, this solution at room temperature stirred one day, vacuum-evaporation.Residue is dissolved in the methylene dichloride (50ml).Under nitrogen atmosphere, dry ice acetone bath cooling, this solution is splashed in methylene dichloride (50ml) suspension of aluminum chloride (4.66g), the gained mixture at room temperature stirs and spends the night.This mixture is poured in the cold 1N hydrochloric acid, used ethyl acetate extraction.Extracting solution is used dried over mgso, vacuum-evaporation with 1N hydrochloric acid, water, 1N sodium hydroxide and salt water washing.Residue is purified through silica gel column chromatography, and mixture (10: 1～5: the 1) wash-out with normal hexane and ethyl acetate obtains 5, two (the p-methylphenyl)-2-cyclopentenes of 5--1-ketone (2.30g).
mp：61-63℃
IR（Nujol）：1690，810，780，760，720cm -1
NMR（CDCl 3，δ）：2，31（6H，s），3.47（2H，t，J＝2.5Hz），6.20-6.35（1H，m），7.10（8H，s），7.75-7.90（1H，m）
Similar approach by preparation 9 can make following compound (preparation 13 and 14).
Preparation 13
5, two (the p-methylphenyl)-2-cyclopentenes of 5--1-alcohol
IR（Film）：3550，3430，810，790，760，740，720cm -1
NMR（CDCl 3，δ）：1.22（1H，d，J＝9.5Hz），2.29（3H，s），2.32（3H，s），2.80-2.95（1H，m），3.30-3.46（1H，m），5.32-5.50（1H，m），5.85-5.95（1H，m），6.05-6.15（1H，m），7.00-7.35（8H，m）
Preparation 14
4,4-dimethyl-2-cyclopentenes-1-alcohol
bp：41-43℃/8 mmHg
IR（Neat）：3320，1035cm -1
NMR(CDCl 3, δ): 1.05(3H, s), 1.16(3H, s), and 1.53(1H, dd, J=4.1Hz and 13.5Hz), 1.54(1H, broadband s), 2.11(1H, dd, J=7.3Hz and 13.5Hz) and, 4.84-4.95
(1H, m), 5.65(1H, dd, J=2.0Hz and 5.5Hz), 5.76(1H, dd, J=1.0Hz and 5.5Hz)
Preparation 15
With 4,4-phenylbenzene-2-cyclopentenes-1-alcohol (0.30g) and triphenyl phosphine (0.43g) mixture in tetracol phenixin (3ml) refluxed 8 hours, cooling, add normal hexane (5ml), this mixture at room temperature stirred 10 minutes, elimination insoluble substance, concentrating under reduced pressure filtrate.Residue is dissolved in the methylene dichloride, and silica gel (1g) is added in this solution, stirs elimination silica gel after 10 minutes, and vacuum-evaporation filtrate gets 4,4-phenylbenzene-2-cyclopentenyl chlorine (0.30g).
IR（Neat）：1595，1490，1445cm -1
NMR(CDCl 3, δ): 2.87(1H, dd, J=4.7Hz and 14.6Hz), 3.22(1H, dd, J=7.3Hz and 14.6Hz), 5.05-5.20(1H, m), 5.98(1H, dd, J=2.1Hz and 5.5Hz), 6.39(1H, dd, J=1.2Hz and 5.5Hz), 7.10-7.40(10H, m)
Preparation 16
The 30cm that dean stark trap is housed at the top fills under the distiller, with 2, the mixture heating up of 2-two cyclopropyl acetaldehyde (9.68g), vinyl carbinol (10.6ml), toluene (9.7ml) and tosic acid (0.05g) 6 days, isolate the 0.9ml water layer during this period, the reaction mixture distillation obtains 2,2-two cyclopropyl-4-pentenals (4.90g) after removing toluene and a small amount of singlings.
bp：43-47℃/0.2mmHg
IR（Neat）：1720cm -1
NMR（CDCl 3，δ）：0.40-0.58（8H，m），0.68-0.85（2H，m），2.12-2.30（2H，m），5.00-5.18（2H，m），5.75-6.00（1H，m），9.47（1H，s）
Preparation 17
Under the room temperature, with the N of cuprous chloride (2.25g) and palladium chloride (0.81g), dinethylformamide (12ml) and water (2.2ml) suspension aerating oxygen stirred 1 hour.22 ℃ under 35 ℃, with 2, the N of 2-two cyclopropyl-4-pentenals (3.74g), dinethylformamide (10ml) solution is added in this mixture, this suspension at room temperature aerating oxygen stirred 4 hours, water (110ml) dilution, and water layer extracts with diethyl ether.Extracting solution washes with water, uses dried over sodium sulfate, vacuum-evaporation.Residue is purified through underpressure distillation, gets 4-oxygen-2,2-two cyclopropyl valerals (1.98g).
bp：80-83℃/0.50mmHg
IR（Neat）：1720cm -1，
NMR（CDCl 3，δ）：0.24-0.60（8H，m），0.80-1.00（2H，m），2.15（3H，s），2.69（2H，s），9.61（1H，s）
Preparation 18
With 4-oxygen-2, diethyl ether (9.4ml) solution of 2-two cyclopropyl valerals (1.88g) is added in the mixture of 5% potassium hydroxide aqueous solution (4.7ml) and tetrahydrofuran (THF) (4.7ml), this mixture was in 38 ℃ to 45 ℃ heating 3 hours, cooling, it is saturated that water layer is chlorinated sodium, and this mixture extracts with diethyl ether.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue is purified through underpressure distillation, carries 4,4-two cyclopropyl-2-cyclopentenes-1-ketone (1.55g).
bp：101-105℃/5mmHg
IR（Neat）：1710cm -1
NMR（CDCl 3，δ）：0.10-0.54（8H，m），0.92-1.12（2H，m），2.04（2H，s），6.07（1H，d，J＝5.7Hz），7.20（1H，d，J＝5.7Hz）
Preparation 19
Under-70 ℃ to-64 ℃, nitrogen atmosphere, with the diisobutylaluminium hydride (hexane solution of 0.94N, 14ml) be added to 4, in diethyl ether (20ml) solution of 4-two cyclopropyl-2-cyclopentenes-1-ketone (1.88g), stir and add ethyl acetate (6ml) after 20 minutes, the dilute hydrochloric acid acidifying of this solution is extracted with diethyl ether.Dried over sodium sulfate is used in extracting solution salt water washing, and vacuum-evaporation gets 4,4-two cyclopropyl-2-cyclopentenes-1-alcohol (0.53g).This compound less stable, thereby do not purify, be directly used in next step reaction.
Embodiment 11
1 ℃ under 3 ℃, methylsulfonyl chloride (0.12ml) and triethylamine (0.21ml) are added to 5, in the acetone soln of 5-phenylbenzene-2-cyclopentenes-1-alcohol (0.30g).Stir and add sodium iodide (0.23g) after 15 minutes, this mixture restir 10 minutes adds TERTIARY BUTYL AMINE (2.67ml) down at-1 ℃ to 2 ℃, in stirred overnight at room temperature.Cold water is added in this mixture, use ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue is dissolved in the ethyl acetate, under the ice bath cooling, 3N hydrochloric acid (1ml) is added in this solution, this mixture stirred 30 minutes, filter and collect the throw out that generates, water and ethyl acetate washing successively, drying, obtain the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride (0.31g).
Mp:265-267 ℃ (decomposition .)
IR（Nujol）：2730，2690，2530，2490，2430cm -1
NMR(DMSO-d 6, δ): 1.37(9H, s), 2.51(1H, dd, J=8.1Hz and 13.3Hz), 3.34(1H, dd, J=7.2Hz and 13.3Hz), 4.44(1H, br m), 6.16(1H, d, J=5.6Hz), 6.72(1H, d, J=5.6Hz), 7.10-7.38(10H, m), 8.89(1H, br s), 9.52(1H, br s)
Similar approach by embodiment 11 can make following compound (embodiment 12 to 23).
Embodiment 12
N-methyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
mp：168-169℃
IR（Nujol）：2680，2430，1600，770，750，700cm -1
NMR(DMSO-d 6, δ): 2.30(1H, dd, J=8.2Hz and 13.4Hz), 2.56(3H, s), 3.24(1H, dd, J=7.0Hz a 13.4Hz), 4.20-4.35(1H, m), 6.06(1H, dd, J=5.7Hz and 1.5Hz), 6.78(1H, dd, J=5.7Hz and 1.9Hz), 7.10-7.45(10H, m), 9.21(2H, broadband s)
Embodiment 13
N-ethyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:209-210 ℃ (by Virahol-re-crystallizing in ethyl acetate)
IR（Nujol）：2680，2450，1595，790，770，750，700cm -1
NMR(DMSO-d 6, δ): 1.22(3H, t, J=7.2Hz), 2.33(1H, dd, J=13.3Hz and 8.3Hz), 3.00(2H, qd, J=7.2Hz and 1.8Hz), 3.25(1H, dd, J=13.3Hz and 7.0Hz), 4.25-4.35(1H, m), 6.07(1H, dd, J=5.7Hz and 1.4Hz), 6.76(1H, dd, J=5.7Hz and 1.9Hz), 7.12-7.46(10H, m), 9.25(2H, broadband s)
Embodiment 14
N-butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:158.5-159 ℃ (by the mixture recrystallization of normal hexane, ethyl acetate and acetone)
IR（Nujol）：2770，2710，2660，2610，2580，2550，2480，2440，1600cm -1
NMR(DMSO-d 6, δ): 0.88(3H, t, J=7.5Hz), 1.33(2H, sextet, J=7.5Hz), 1.61(2H, quintet, J=7.5Hz), 2.35(1H, dd, J=8.5Hz and 13.5Hz), 2.90(2H, m), 3.26(1H, dd, J=7.0Hz and 13.5Hz), 4.32(1H, m), 6.09(1H, d, J=5.5Hz), 6.76(1H, dd, J=2.0Hz and 5.5Hz), 7.1-7.4(10H, m), 9.25(2H, br s)
Embodiment 15
N, N-dimethyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:189-190 ℃ (by Virahol-acetone recrystallization)
IR（Nujol）：2550，2430，780，760，700cm -1
NMR(DMSO-d 6, δ): 2.44(1H, dd, J=13.6Hz and 8.1Hz), 2.74(6H, s), 3.20(1H, dd, J=13.6Hz a 7.1Hz), 4.40-4.55(1H, m), 6.14(1H, dd, J=1.6Hz and 5.8Hz), 6.85(1H, dd, J=2.0Hz and 5.8Hz), 7.20-7.40(10H, m), 10.73(1H, broadband s)
Embodiment 16
N, N-diethyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:186-187 ℃ (by Virahol-re-crystallizing in ethyl acetate)
IR（Nujol）：2520，2470，1600，790，750，700cm -1
NMR(DMSO-d 6, δ): 1.23(6H, t, J=7.12Hz), 2.35-2.47(1H, m), 3.02-3.30(5H, m), 4.53-4.72(1H, m), and 6.13(1H, d, J=5.8Hz), 6.89(1H, d, J=5.8Hz), 7.18-7.52(10H, m), 10.03(1H, broadband s)
Embodiment 17
N-benzyl-N-methyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
mp：162-165℃
IR（Nujol）：3050，2500，780，760，750，700cm -1
NMR（DMSO-d 6，δ）：2.35-2.70（1H，m），3.10-3.45（1H，m），3.34（3H，s），4.10-4.30（1H，m），4.40-4.70（2H，m），6.15-6.30（1H，m），6.75-7.00（1H，m），7.10-7.40（10H，m），7.40-7.55（3H，m），7.55-7.70（2H，m），10.80-11.20（1H，m）
Embodiment 18
N-benzyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:201-204 ℃ (by methyl alcohol-Virahol-re-crystallizing in ethyl acetate)
IR（Nujol）：1600，1580，760，700cm -1
NMR(DMSO-d 6, δ): 2.45(1H, dd, J=13.2Hz and 8.6Hz), 3.28(1H, dd, J=13.2Hz and 6.8Hz), 4.21(2H, broadband s), 4.30-4.50(1H, m), 6.15(1H, d, J=5.7Hz), 6.77(1H, dd, J=5.7Hz and 1.7Hz), 7.10-7.35(10H, m), 7.35-7.55(3H, m), 7.55-7.80
Embodiment 19(2H, m), 9.82(2H, broadband s)
N-(1,1-dimethyl-2-hydroxyethyl)-4,4-phenylbenzene-2-cyclopentamine hydrochloride
mp：176-177℃
IR（Nujol）：3400，1600cm -1
NMR(CDCl 3, δ): 1.39(6H, s), 2.60(3H, s), 2.77(1H, dd, J=13.3Hz and 8.5Hz), 3.23(1H, dd, J=13.3Hz and 6.9Hz), 3.62(2H, s), 4.35(1H, brs), 6.19(1H, dd, J=5.7Hz and 1.0Hz), 6.43(1H, dd, J=5.7Hz and 2.0Hz), 7.12-7.36(10H, m), 8.17-8.56(2H, m)
Embodiment 20
N-[(1,1-dimethyl-2-(N-xylyl amino) ethyl]-4,4-phenylbenzene-2-cyclopentamine dihydrochloride
Mp:196-197 ℃ of (decomposition) (by ethanol-re-crystallizing in ethyl acetate)
IR（Nujol）：2750，2600，2500，1600，1580，790，750，700cm -1
NMR(DMSO-d 6, δ): 1.40(3H, s), 1.59(3H, s), 2.45-2.70(1H, m), 2.89(3H, s), 2.82(1H, dd, J=6.9Hz and 13.2Hz), 3.35-3.90(2H, m), 4.20-4.60(1H, m), 4.45(2H, s), 6.11(1H, d, J=5.3Hz), 6.74(1H, d, J=5.5Hz), 6.95-7.85(15H, m), 9.64(1H, broadband s), 10.23(1H, broadband s), 11.03(1H, broadband s)
Embodiment 21
N-(1-ethyl hexamethylene-1-yl)-4,4-phenylbenzene-2-cyclopentamine hydrochloride
Mp:228-234 ℃ (decomposition) (by methyl alcohol-ethanol-re-crystallizing in ethyl acetate)
IR（Nujol）：1580，780，770，700cm -1
NMR(DMSO-d 6, δ): 0.89(3H, t, J=7.4Hz), 1.00-2.10(12H, m), 2.58(1H, dd, J=13.4Hz and 8.2Hz), 3.28(1H, dd, J=13.4Hz and 6.1Hz), 4.42(1H, broadband s), 6.14(1H, broadband d, J=5.7Hz), 6.73(1H, broadband d, J=3.9Hz), 7.10-7.50(10H, m), 8.55-8.80(1H, m), 8.90-9.20(1H, m)
Embodiment 22
4-(4,4-phenylbenzene-2-cyclopentenyl) morpholine hydrochloride
Mp:285-288 ℃ of (decomposition) (by recrystallizing methanol)
IR（Nujol）：2520，2440，790，760，700cm -1
NMR(DMSO-d 6, δ): 3.00-3.82(8H, m), 3.90-4.08(2H, m), 4.48-4.60(1H, m), 6.19-6.30(1H, m), 6.84-6.95(1H, m), 7.15-7.42(10H, m), 10.50-10.72(1H, broadband s)
Embodiment 23
The N-tertiary butyl-4, two (the p-methylphenyl)-2-cyclopentamine hydrochlorides of 4-
Mp:265-267 ℃ (by ethanol-Virahol recrystallization)
IR（Nujol）：2760，2630，820，800，720cm -1
NMR(DMSO-d 6, δ): 1.36(9H, s), 2.25(3H, s), 2.26(3H, s), 2.46(1H, dd, J=7.9Hz and 13.4Hz), 3.26(1H, dd, J=7.1Hz and 13.4Hz), 4.39(1H, broadband s), 6.10(1H, dd, J=1.3Hz and 5.7Hz), 6.65(1H, dd, J=1.8Hz and 5.7Hz), 7.09(4H, s), 7.12(4H, s), 8.82(1H, broadband s), 9.38(1H, broadband s)
Embodiment 24
Under the ice bath cooling, methylsulfonyl chloride (0.27ml) and triethylamine (0.49ml) are added to 4, in acetone (5ml) solution of 4-two cyclopropyl-2-cyclopentenes-1-alcohol (0.52g), stir and add sodium iodide (0.52g) after 10 minutes, this mixture restir 10 minutes, adding TERTIARY BUTYL AMINE (6.4ml), in stirred overnight at room temperature, vacuum evaporating solvent adds cold water then, this mixture ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue is dissolved in the ethyl acetate, add again hydrogenchloride ethanolic soln (8.9N, 0.5ml), vacuum-evaporation.Residue gets the N-tertiary butyl-4 through the diethyl ether crystallization, 4-two cyclopropyl-2-cyclopentamine hydrochloride (0.51g), and these crystal obtain straight product (0.41g) with the mixture recrystallization of Virahol and ethyl acetate.
mp：202.5-203.5℃
IR（Nujol）：2750，2625，2500，2455，2430，1580cm -1
NMR(CDCl 3, δ) :-0.10-0.15(2H, m), 0.15-0.64(6H, m), 0.64-0.85(1H, m), 0.96-1.15(1H, m), 1.50(9H, s), 2.19(1H, dd, J=7.6Hz and 12.9Hz), 2.27(1H, dd, J=8.0Hz and 12.9Hz), 4.08-4.28(1H, m), 5.41(1H, dd, J=2.2Hz and 5.8Hz), 6.22(1H, dd, J=1.5Hz and 5.8Hz), 9.37(2H, broadband s)
Embodiment 25
With 4, diisopropyl ether (3ml) mixture of 4-phenylbenzene-2-cyclopentenes-1-alcohol (0.30g) and carbon tetrabromide (0.55g) refluxed 30 minutes, the cooling back adds normal hexane (10ml) and diisopropyl ether (2ml), the elimination insoluble substance, be lower than 30 ℃ of following vacuum-evaporation filtrates, TERTIARY BUTYL AMINE (2ml) and acetone (4ml) are added in the residue, refluxed 30 minutes, then cooling.This mixture concentrating under reduced pressure is purified with silica gel column chromatography, with chloroform and methanol mixture wash-out, gets the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (0.26g).
Its physical data is identical with embodiment 1 compound.
Embodiment 26
Similar approach by embodiment 25 can make the N-tertiary butyl-4,4-dimethyl-2-cyclopentamine hydrochloride
Mp:194 ℃ (decomposition) (by mixture recrystallization of diethyl ether and chloroform)
IR（Nujol）：3400，2760，2690，2640，2470cm -1
NMR(CDCl 3, δ): 1.05(3H, s), 1.26(3H, s), 1.51(9H, s), 2.17(1H, dd, J=8.0Hz and 13.3Hz), 2.37(1H, dd, J=7.3Hz and 13.3Hz), 4.26-4.45(1H, m), 5.78(1H, dd, J=2.1Hz and 5.6Hz), 6.03(1H, dd, J=1.7Hz and 5.6Hz), 9.35(2H, br s)
Embodiment 27
With 4, the mixture of 4-phenylbenzene-2-cyclopentenyl chlorine (0.20g), TERTIARY BUTYL AMINE (2ml) and catalytic amount sodium iodide (being dissolved in the 4ml acetone) refluxed 15 hours, then cooling.This mixture adds entry after vacuum-evaporation, use ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture wash-out, gets the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (0.15g).
The physical data of this compound is identical with embodiment 1 compound.
Embodiment 28
With 4, the sodium iodide of 4-phenylbenzene-2-cyclopentenyl chlorine (0.30g), TERTIARY BUTYL AMINE (1.24ml), catalytic amount and the mixture of 18-hat-6 in methylene dichloride (3ml) refluxed cooling then 47 hours.Solvent removed in vacuo adds entry, this mixture ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, reduction vaporization.Under the ice bath cooling, ethyl acetate (5ml) and 3N hydrochloric acid (2ml) are added in the residue, this mixture stirred 3 hours, filter the collecting precipitation thing, successively with ethyl acetate, water, ethyl acetate washing, drying, get the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride (0.28g).
The physical data of this compound is identical with embodiment 11 compounds.
Embodiment 29
With 4, acetone (5ml) mixture of 4-phenylbenzene-2-cyclopentenyl chlorine (0.26g) and sodium iodide (0.15g) refluxed 90 minutes, the elimination insoluble substance, TERTIARY BUTYL AMINE (1.5ml) and acetone (5ml) are added in the filtrate, this solution refluxed 2 hours, cooling adds entry after the solvent removed in vacuo, use ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, reduction vaporization.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture wash-out, gets the N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine (0.25g).
The physical data of this compound is identical with embodiment 1 compound.
Embodiment 30
Under the room temperature, (0.33g) is added to 4 with triphenyl phosphine, in acetone (3ml) solution of 4-phenylbenzene-2-cyclopentenyl nitrine (0.30g), refluxed 21 hours, after the cooling, removal of solvent under reduced pressure, methyl alcohol (3ml) solution of adding sodium borohydride (0.22g), stir after 20 minutes, add salt solution and ethyl acetate.Isolate organic layer, use the salt water washing, use dried over mgso, vacuum-evaporation.Residue dodges chromatogram through silicagel column purifies, with chloroform and methanol mixture wash-out, and row N-sec.-propyl-4,4-phenylbenzene-2-cyclopentamine (0.26g).
NMR(CDCl 3, δ): 1.07(3H, d, J=6.20Hz), 1.09(3H, d, J=6.20Hz), 1.90(1H, br s), 2.15(1H, dd, J=7.05Hz and 13.14Hz), 1.85-3.14(2H, m), 4.00-4.15(1H, m), 5.60(1H, dd, J=5.61Hz and 1.74Hz), 6.28(1H, dd, J=5.61Hz and 1.84Hz), 7.10-7.40(10H, m)
The methanol solution of methylsulfonic acid (92mg) is added in the chloroformic solution of the above-mentioned unhindered amina compound (0.26g) that obtains vacuum-evaporation.Residue is developed with the mixture of diethyl ether and ethyl acetate, obtains its mesylate (0.26g).
mp：148-150℃
IR（Nujol）：1610，1490cm -1
NMR(CDCl 3, δ): 1.38(3H, d, J=6.2Hz), 1.39(3H, d, J=6.2Hz), 2.52(3H, s), 2.64(1H, dd, J=8.7Hz and d 13.0Hz), 3.19(1H, dd, J=6.7Hz and d 13.0Hz), 3.20-3.50(1H, m), 4.35(1H, br s), 6.12(1H, d, J=5.7Hz), 6.42(1H, d, J=5.7Hz), 7.10-7.40(10H, m), 8.75(2H, br s)
Embodiment 31
With 4,4-phenylbenzene-2-cyclopentenyl chlorine (0.60g), 4-diethylin-1, acetone (5ml) mixture of 1-dimethyl-2-butyne amine (0.79g) and catalytic amount sodium iodide refluxed 8 hours, after the cooling, removal of solvent under reduced pressure.Residue is purified through silica gel column chromatography, with chloroform and methyl alcohol and mixture wash-out, obtains N-[4-diethylin-1,1-dimethyl-2-butyne base]-4,4-phenylbenzene-2-cyclopentamine (0.54g).The above-mentioned unhindered amina that obtains is dissolved in the chloroform, and (0.18g/ml, 1ml), this solution with the mixture development of ethanol and Virahol, obtains its hydrochloride (0.45g) through vacuum-evaporation to the methanol solution of adding hydrogenchloride.
Mp:225 ℃ of (decomposition) (by ethyl alcohol recrystallization)
IR（Nujol）：2725，2300cm -1
NMR(D 2O, δ): 1.26(6H, t, J=7.3Hz), 1.77(6H, s), 2.57(1H, dd, J=8.2Hz and 13.4Hz), 3.23(4H, q, J=7.3Hz), 3.47(1H, dd, J=7.0Hz and 13.4Hz), 4.17(2H, s), 4.60-4.80(1H, m), 6.15(1H, dd, J=1.2Hz and 5.7Hz), 6.85(1H, dd, J=1.8Hz and 5.7Hz), 7.24-7.50(10H, m)
Embodiment 32
Under-70 ℃ to-60 ℃ and nitrogen atmosphere, (hexane solution of 0.94M 28.5ml) is added in diethyl ether (20ml) solution of 2-cyclopentenes-1-ketone (2.0g) with diisobutylaluminium hydride.Stir after 1 hour, add ethyl acetate (11.9ml), ethyl acetate extraction is used in the dilute hydrochloric acid acidifying of this solution.Dried over mgso is used in extracting solution salt water washing, and distillation removes and desolvates.Residue is dissolved in the acetone (50ml), adds methylsulfonyl chloride (1.88ml) and triethylamine (3.39ml) under the ice bath cooling.Stir after 10 minutes, add sodium iodide (3.63g), this mixture stirred 10 minutes, added TERTIARY BUTYL AMINE (49ml), in stirred overnight at room temperature.Distillation removes the back of desolvating and adds cold water, and with this mixture of ethyl acetate extraction, (8.9N 3ml) is added in the extracting solution concentrating under reduced pressure with the ethanolic soln of hydrogenchloride.Residue obtains tert-butylamine salt hydrochlorate (0.40g) with the crystalline mixture of diethyl ether and Virahol.Remove by filter gained salt, filtrate is through vacuum-evaporation.Residue obtains the N-tertiary butyl-2-cyclopentamine hydrochloride (0.74g) with the crystalline mixture of diethyl ether and ethyl acetate, and these crystal obtain pure compound (0.26g) with the mixture recrystallization of Virahol and ethyl acetate.
Mp:178-180 ℃ (decomposition .)
IR（Nujol）：2770，2650，2500，2440cm -1
NMR（CDCl 3，δ）：1.52（9H，s），2.20-2.64（3H，m），2.64-2.90（1H，m），4.24（1H，br s），6.00-6.18（2H，m），9.24（2H，br s）
Embodiment 33
The methanol solution of methylsulfonic acid (0.16g) is added to the N-tertiary butyl-3, in the chloroform and methanol solution of 3-phenylbenzene cyclopentamine (0.49g), add ethyl acetate behind the vacuum evaporating solvent, after leaving standstill 2 hours, collect the throw out that generates, obtain the N-tertiary butyl-3,3-phenylbenzene cyclopentamine mesylate (0.51g).
mp：243-244℃
IR（Nujol）：1610，1490cm -1
NMR（DMSO-d 6，δ）：1.30（9H，s），1.88-2.40（4H，m），2.32（3H，s），2.60-2.78（1H，m），3.20-3.36（1H，m），3.48-3.70（1H，m），7.05-7.50（10H，m），8.45（2H，br s）
Embodiment 34
Under-70 ℃ to-60 ℃, methylene dichloride (5ml) solution of titanium tetrachloride (0.50g) is splashed into 4, in methylene dichloride (9ml) solution of 4-phenylbenzene-2-cyclopentenes-1-ketone (0.40g), TERTIARY BUTYL AMINE (0.75g), stir after 2 hours, add sodium borohydride (0.35g) and methyl alcohol (6ml) successively in 0 ℃.Behind the restir 0.5 hour, with diatomite elimination throw out, concentrating under reduced pressure filtrate is added to the 1N aqueous sodium hydroxide solution in the residue, uses ethyl acetate extraction.Extracting solution salt water washing is used dried over mgso, vacuum-evaporation.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture wash-out, obtains the N-tertiary butyl-4 respectively, the 4-phenylbenzene-2-cyclopentamine (0.13g) and N-tertiary butyl-3,3-phenylbenzene cyclopentamine (0.19g).
The N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine
NMR(CDCl 3, δ): 0.80-1.40(1H, br m), 1.12(9H, s), 2.04(1H, dd, J=7.6Hz and 13.0Hz), 3.09(1H, dd, J=6.8Hz and 13.0Hz), 3.94-4.10(1H, m), 5.85(1H, dd, J=1.7Hz and 5.6Hz), 6.21(1H, dd, J=2.0Hz and 5.6Hz), 7.09-7.38(10H, m)
The N-tertiary butyl-3,3-phenylbenzene cyclopentamine
NMR（CDCl 3，δ）：1.03（9H，s），1.49-1.72（1H，m），1.93-2.63（5H，m），2.74-2.89（1H，m），3.14-3.37（1H，m），7.02-7.14（10H，m）
Embodiment 35
Similar approach by embodiment 34 can make the N-tertiary butyl-4,4-phenylbenzene-2-hexamethylene enamine mesylate.
Mp:227-229 ℃ (by the mixture recrystallization of ethanol and diethyl ether)
NMR(CDCl 3, δ): 1.43(9H, s), 1.75-2.33(4H, m), 2.50(3H, s), 3.60-3.90(1H, m), and 6.09(1H, dd, J=10Hz and 2Hz), 6.36(1H, d, J=10Hz), 7.00-7.30(10H, m), 8.30(2H, br s)
Embodiment 36
Under-70 ℃ to-50 ℃, methylene dichloride (6ml) solution of titanium tetrachloride (0.66g) is splashed into 4, in methylene dichloride (20ml) solution of 4-phenylbenzene hexamethylene-1-ketone (1.15g) and TERTIARY BUTYL AMINE (2.01g), stir after 30 minutes, add sodium borohydride (0.34g) and methyl alcohol (20ml).This mixture restir adds entry (5ml) after 30 minutes, with diatomite elimination throw out, concentrating under reduced pressure filtrate is used ethyl acetate extraction.Extracting solution salt water washing is used dried over sodium sulfate, vacuum-evaporation.Residue (1.47g) is dissolved in the ethyl acetate, this solution is added in methyl alcohol (3ml) solution of methylsulfonic acid (441mg), after the room temperature standing over night, collects the throw out that generates, obtain the N-tertiary butyl-4,4-phenylbenzene hexahydroaniline mesylate (1.20g).
mp：253-255℃
NMR（CDCl 3，δ）：1.36（9H，s），1.60-2.95（9H，m），2.35（3H，s），6.96-7.35（10H，m），7.90（2H，br s）
Embodiment 37
Similar approach by embodiment 36 can make the N-tertiary butyl-3,3-hexichol basic ring butylamine mesylate.
mp：197-198℃
IR（Nujol）：1590，1485cm -1
NMR（CDCl 3，δ）：1.37（9H，s），2.33（3H，s），3.22（4H，d，J＝8.29Hz），3.67（1H，pentet，J＝8.29Hz），7.06-7.43（10H，m），8.71（2H，s）
Similar approach by embodiment 34 can make following compound (embodiment 38 to 55).
Embodiment 38
N-methyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：2680，2430，1600，770，750，700cm -1
Embodiment 39
N-ethyl-4,4-phenylbenzene-cyclopentamine hydrochloride
IR（Nujol）：2680，2450，1595，790，770，750，700cm -1
Embodiment 40
N-butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：2770，2710，2660，2610，2580，2550，2480，2440，1600cm -1
Embodiment 41
N, N-dimethyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：2550，2430，780，760，700cm -1
Embodiment 42
N, N-diethyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：2520，2470，1600，790，750，700cm -1
Embodiment 43
N-benzyl-N-methyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：3050，2500，780，760，750，700cm -1
Embodiment 44
N-benzyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：1600，1580，760，700cm -1
Embodiment 45
N-(1,1-dimethyl-2-hydroxyethyl)-4,4-phenylbenzene-2-cyclopentamine mesylate
IR（Nujol）：3400，1600cm -1
Embodiment 46
N-[1,1-dimethyl-2-(N-methyl-benzyl amino) ethyl]-4,4-phenylbenzene-2-cyclopentamine dihydrochloride
IR（Nujol）：2750，2600，2500，1600，1580，790，750，700cm -1
Embodiment 47
N-(1-ethyl hexamethylene-1-yl)-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：1580，780，770，700cm -1
Embodiment 48
4-(4,4-phenylbenzene-2-cyclopentenyl) morpholine hydrochloride
IR（Nujol）：2520，2440，790，760，700cm -1
Embodiment 49
The N-tertiary butyl-4, two (the p-methylphenyl)-2-cyclopentamine hydrochlorides of 4-
IR（Nujol）：2760，2630，820，800，720cm -1
Embodiment 50
The N-tertiary butyl-4,4-two cyclopropyl-2-cyclopentamine hydrochloride
IR（Nujol）：2750，2625，2500，2455，2430，1580cm -1
Embodiment 51
The N-tertiary butyl-4,4-dimethyl-2-cyclopentamine hydrochloride
IR（Nujol）：3400，2760，2690，2640，2470cm -1
Embodiment 52
N-sec.-propyl-4,4-phenylbenzene-2-cyclopentamine mesylate
IR（Nujol）：1610，1490cm -1
Embodiment 53
N-[4-diethylin-1,1-dimethyl-2-butyne base]-4,4-phenylbenzene-2-cyclopentamine hydrochloride
IR（Nujol）：2725，2300cm -1
Embodiment 54
The N-tertiary butyl-2-cyclopentamine hydrochloride
IR（Nujol）：2770，2650，2500，2440cm -1
Embodiment 55
1-(4,4-phenylbenzene-2-cyclopentenyl) piperazine dihydrochloride
IR（Nujol）：1590，770，750，700cm 1
Embodiment 56
Prepare 1-(4 as follows; 4-phenylbenzene-2-cyclopentenyl) piperazine dihydrochloride; promptly press the similar approach of embodiment 11; make 5; the pure and mild 1-formyl piperazine reaction of 5-phenylbenzene-2-cyclopentenes-1-; obtain 1-(4,4-phenylbenzene-2-cyclopentenyl)-the 4-formyl piperazine, eliminate formyl radical with ordinary method then.
mp：244℃（dec.）
IR（Nujol）：1590，770，750，700cm -1
NMR(CD 3OD, δ): 2.58(1H, dd, J=13.9Hz and 7.7Hz), 3.39(1H, dd, J=13.9Hz and 7.5Hz), 3.63(8H, broadband s), 4.76(1H, pseudo t, J=7.5Hz), 6.17(1H, dd, J=5.7Hz and 1.6Hz), 6.87(1H, dd, J=5.7Hz and 1.9Hz), 7.10-7.40(10H, m)
Similar approach by embodiment 11 or 25 or 27 can make following compound (embodiment 57 to 60)
Embodiment 57
The N-tertiary butyl-3,3-phenylbenzene cyclopentamine
NMR（CDCl 3，δ）：1.03（9H，s），1.49-1.72（1H，m），1.93-2.63（5H，m），2.74-2.89（1H，m），3.14-3.37（1H，m），7.02-7.14（10H，m）
Embodiment 58
The N-tertiary butyl-4,4-phenylbenzene hexamethylene enamine mesylate
mp：227-229℃
Embodiment 59
The N-tertiary butyl-4,4-phenylbenzene hexahydroaniline mesylate
mp：253-255℃
Embodiment 60
The N-tertiary butyl-3,3-hexichol basic ring butylamine mesylate
IR（Nujol）：1590，1485cm -1
Similar approach by embodiment 8 can make following compound (embodiment 61 to 63).
Embodiment 61
The N-tertiary butyl-3,3-phenylbenzene cyclopentamine
NMR（CDCl 3，δ）：1.03（9H，s），1.49-1.72（1H，m），1.93-2.63（5H，m），2.74-2.89（1H，m），3.14-3.37（1H，m），7.02-7.14（10H，m）
Embodiment 62
The N-tertiary butyl-4,4-phenylbenzene hexahydroaniline mesylate
mp：253-255℃
Embodiment 63
The N-tertiary butyl-3,3-hexichol basic ring butylamine mesylate
IR（Nujol）：1590，1485cm -1
Preparation 20
Under nitrogen atmosphere and dry ice acetone bath cooling, titanium isopropoxide (IV) (0.63ml) is added to 5, the active powder 0.5g of 5-phenylbenzene-2-cyclopentenes-1-alcohol (5.0g), D-dimethyl tartrate (0.49g), molecular sieve 4A() in methylene dichloride (50ml) suspension, stir after 30 minutes, add tertbutyl peroxide (2 of 3.0M, 2,4-trimethylpentane solution, 3.57ml).Then, place refrigerator to preserve 4 days in this mixture, pour into again in ice and the water (50ml), the emulsion that generates is filtered by diatomaceous earth filler, isolate organic layer, use the salt water washing, use dried over mgso, vacuum-evaporation, residue is purified through silica gel column chromatography, obtain (+)-5,5-phenylbenzene-2-cyclopentenes-1-alcohol (1.84g, [α] 21.2 D=+100.8 °, C=1.19, CH 3OH) and (-)-rel-(1R, 2R, 3S)-2,3-epoxy-5,5-hexichol basic ring penta-1-alcohol * [rich (-) isomer mixture] (1.27g, [α] 22.4 D=-150.5 °, C=0.6276, CH 2Cl 2).
Figure 911012184_IMG52
Preparation 21
Similar approach by preparation 20 can make (+)-rel-(1R, 2R, 3S)-2,3-epoxy-5,5-hexichol basic ring penta-1-alcohol [rich (+) isomer mixture; [α] 22 D=+45.34 ° of (C=0.743, CH 3OH)] and (-)-5,5-phenylbenzene-2-cyclopentenes-1-alcohol.
Preparation 22
Crude product (+)-rel-(1R, 2R, 3S)-2, and 3-epoxy-5, the method for purification of 5-hexichol basic ring penta-1-alcohol [rich (-) isomer mixture] is as described below:
Crude product (1.21g) obtains its racemoid (0.48g, mp 140-141 ℃) with ethyl acetate (3ml) recrystallization, concentrating under reduced pressure filtrate, and residue obtains pure (-) isomer (0.52g) with diisopropyl ether (7ml) crystallization.
mp：92.5-94℃
[α] 21.2 D＝-298.6°（C＝0.66，CH 2Cl 2）
IR（Nujol）：3420cm -1
NMR（CDCl 3，δ）：1.61（1H，d，J＝12.3Hz），2.42（1H，d，J＝15.1Hz），3.47（1H，d，J＝15.1Hz），3.66（2H，pseudo s），4.96（1H，d，J＝12.3Hz），7.07-7.35（10H，m）
Preparation 23
By similar approach purification crude product (+)-rel-(1R of preparation 22,2R, 3S)-2,3-epoxy-5,5-hexichol basic ring penta-1-alcohol
mp：92-93℃
[α] 22 D＝+268.17°（C＝0.465，CH 2Cl 2）
IR（Nujol）：3450，3420，770，750，700cm -1
NMR（CDCl 3，δ）：1.61（1H，d，J＝12.3Hz），2.42（1H，d，J＝15.1Hz），3.47（1H，d，J＝15.1Hz），3.66（2H，pseudo s），4.96（1H，d，J＝12.3Hz），7.07-7.35（10H，m）
Preparation 24
Prepare 20 resulting (-)-rel-(1R, 2R, 3S)-2,3-epoxy-5,5-hexichol basic ring penta-1-alcohol [rich (-) isomer mixture] is used re-crystallizing in ethyl acetate, obtains (±)-rel-(1R 2R, 3S)-2,3-epoxy-5,5-hexichol basic ring penta-1-alcohol (racemic mixture).
mp：136-137℃
IR（Nujol）：3420，3050，800，770，750，740，700cm -1
Embodiment 64
The ice bath cooling down, titanium isopropoxide (IV) (0.46ml) is added to (-)-rel-(1R, 2R, 3S)-2,3-epoxy-5 in the methylene dichloride (3ml) of 5-hexichol basic ring penta-1-alcohol (297mg) and Virahol (1.2ml) solution, stirs and adds TERTIARY BUTYL AMINE (0.25ml) after 30 minutes, this mixture is in stirred overnight at room temperature, vacuum evaporated solution.Residue is dissolved in the diethyl ether (3ml), in ice bath, be added to 3N hydrochloric acid (1.66ml) in this solution and stirred 3 hours, filter and collect the throw out that generates, with diethyl ether (3ml) washing, drying obtains (-)-rel-(1R, 2S, 3R)-and uncle's 3-fourth amino-5,5-phenylbenzene pentamethylene-1,2-diol hydrochloride (0.36g).
Mp:279-281 ℃ (decomposition .)
[α] 19.2 D＝-77.1°（C＝0.31，MeOH）
IR（Nujol）：3420，3350，3160cm -1
NMR(DMSO-d 6, δ): 1.36(9H, s), 2.63(1H, dd, J=14.0Hz and 7.7Hz), 3.12(1H, dd, J=14.0Hz and 9.9Hz), 3.48-3.72(1H, br s), 4.09-4.26(1H, m), 4.68-4.84(1H, m), 5.15(1H, d, J=5.8Hz), 5.23(1H, d, J=4.9Hz), 7.00-7.50(10H, m), 8.78(1H, br s), 9.17(1H, br s)
Similar approach by embodiment 64 can make following compound (embodiment 65 to 68).
Embodiment 65
(+)-rel-(1R, 2S, 3R)-and uncle's 3-fourth amino-5,5-phenylbenzene pentamethylene-1,2-diol hydrochloride
[α] 21 D＝+74.6°（C＝0.335，MeOH）
mp：288℃
IR（Nujol）：3520，3320，1590，770，740，700cm -1
NMR(DMSO-d 6, δ): 1.35(9H, s), 2.52-2.70(1H, m), 3.01-3.21(1H, m), 3.50-3.72(1H, m), 4.08-4.21(1H, m), 4.77(1H, t, J=4.8Hz), 5.15(1H, d, J=5.8Hz), 5.21(1H, d, J=4.8Hz), 7.00-7.52(10H, m), 8.71(1H, broadband s), 9.05(1H, broadband s)
Embodiment 66
(±)-rel-(1R, 2S, 3R)-and uncle's 3-fourth amino-5,5-phenylbenzene pentamethylene-1,2-diol hydrochloride
Mp:278-279 ℃ (decomposition)
IR（Nujol）：3500，3300，3190，1580，770，740，700cm -1
NMR(DMSO-d 6, δ): 1.36(9H, s), 2.63(1H, dd, J=14.0Hz and 7.7Hz), 3.12(1H, dd, J=14.0Hz and 9.9Hz), 3.61(1H, broadband s), 4.10-4.20(1H, m), 4.70-4.80(1H, m), 5.15(1H, d, J=5.8Hz), 5.23(1H, d, J=4.9Hz), 7.00-7.50(10H, m), 8.78(1H, broadband s), 9.17(1H, broadband s)
Embodiment 67
(±)-rel-(1R, 2S, 3R)-and 3-isopropylamino-5,5-phenylbenzene pentamethylene-1,2-diol hydrochloride
Mp:283-285 ℃ (decomposition .)
IR（Nujol）：3500，3300，770，750，700cm -1
NMR(DMSO-d 6, δ): 1.28(6H, d, J=5.1Hz), 2.35(1H, dd, J=13.6Hz and 9.0Hz), 3.06(1H, dd, J=13.6Hz and 9.0Hz), 3.25-3.65(2H, m), 4.15-4.30(1H, m), 4.71(1H, pseudo t, J=5.7Hz), 5.09(1H, d, J=6.3Hz), 5.16(1H, d, J=4.8Hz), 7.02-7.58(10H, m), 9.06(2H, broadband s)
Embodiment 68
(±)-rel-(1R, 2S, 3R)-and 3-diethylin-5,5-phenylbenzene pentamethylene-1,2-diol hydrochloride
Mp:243-245 ℃ (decomposition .)
IR（Nujol）：3470，3150，800，760，750，720，710，700cm -1
NMR(DMSO-d 6, δ): 1.08-1.35(6H, m), 2.38(1H, dd, J=13.2Hz and 10.0Hz), 2.94-3.10(5H, m), 3.42-3.65(1H, m), 4.28-4.42(1H, m), 4.67(1H, dd, J=6.7Hz and 5.8Hz), 5.18(1H, d, J=6.7Hz), 5.26(1H, d, J=4.8Hz), 7.02-7.50(10H, m), 10.56(1H, broadband s)
Embodiment 69
(0.45ml) is added to (-)-rel-(1R with trimethyl orthoformate, 2S, 3R)-uncle's 3-fourth amino-5,5-phenylbenzene pentamethylene-1, in methylene dichloride (6ml) suspension of 2-diol hydrochloride (299mg) and tosic acid-hydrate (16mg), this mixture is in stirred overnight at room temperature, and evaporation removes and desolvates.
Residue is dissolved in the dimethylbenzene (9ml), refluxes 3 hours, and the cooling back adds 2.5N sodium hydroxide solution (1.0ml), and this mixture stirred 1 hour, isolated organic layer, water ethyl acetate extraction, the organic layer that vacuum-evaporation merges.Residue is purified through silica gel column chromatography, with chloroform and methanol mixture wash-out, obtains (-)-the N-tertiary butyl-4 4-phenylbenzene-2-cyclopentamine (130mg).
This amine is suspended in the mixture of Virahol (0.4ml) and water (0.2ml), in ice bath, be added to concentrated hydrochloric acid (0.065ml) in this suspension and stirred 5 hours, filter and collect the throw out that generates, wash with 30% isopropanol water solution (0.4ml), dry, obtain (-)-the N-tertiary butyl-4 4-phenylbenzene-2-cyclopentamine hydrochloride (89mg).
The physical data of this compound is identical with embodiment 10 compounds.
Embodiment 70
Similar approach by embodiment 69 can make (+)-N-tertiary butyl-4,4-phenylbenzene-2-cyclopentamine hydrochloride.
mp：259-260℃（dec.）
[α] 23 D＝+189.16°（C＝0.60，MeOH）
IR（Nujol）：3400，2750，2700，1600，780，770，700cm -1
NMR(DMSO-d 6, δ): 1.36(9H, s), 2.34-2.47(1H, m), 3.33-3.46(1H, m), 4.44-4.61(1H, m), 6.03(1H, broadband d, J=5.6Hz), 6.76(1H, broadband d, J=5.6Hz), 7.15-7.25(10H, m), 8.50-8.68(1H, m), 8.90-9.15(1H, m)

Claims (1)

1, the method for preparing substituted amine compound shown in the following formula or its salt:
Figure 911012184_IMG3
In the formula:
Formula
Figure 911012184_IMG4
Group be ring (rudimentary) alkyl or ring (rudimentary) alkenyl,
R 1And R 2The hydrogen of respectively doing for oneself, low alkyl group, ring (rudimentary) alkyl maybe can have one or more suitable substituent aryl,
R 3Be to have one or more suitable substituent low alkyl groups, can have one or more suitable substituent low-grade alkynyls, maybe can have one or more suitable substituent ring (rudimentary) alkyl,
R 4Be hydrogen, low alkyl group or aryl (rudimentary) alkyl, wherein
R 3And R 4Can be joined together to form and can have one or more suitable substituent heterocyclic groups,
R 5And R 6Respectively do for oneself hydrogen or hydroxyl,
But it is necessary
(i) work as formula
Figure 911012184_IMG5
Group is a cyclopentyl, R 1And R 2Respectively do for oneself and to have the phenyl of chlorine, R 5And R 6When respectively doing for oneself hydrogen, R 3Be the tertiary butyl,
(ii) work as formula Group is a cyclohexyl, R 1And R 2The phenyl of respectively doing for oneself, R 5When being hydrogen, R 3Be the tertiary butyl,
(iii) work as formula Group is a cyclohexenyl, R 1And R 2The phenyl of respectively doing for oneself, R 5And R 6When respectively doing for oneself hydrogen, R 3Be the tertiary butyl,
(iv) working as formula A group is cyclopentenyl, R 1, R 2, R 5And R 6When respectively doing for oneself hydrogen, R 3Be the tertiary butyl,
This method comprises
(i) following formula: compound and formula The compound or its salt reaction:
In the formula:
Formula Group, R 1, R 2, R 3, R 4, R 5And R 6Definition the same,
X is a leavings group,
(ii) following formula: compound and formula The compound or its salt reaction:
Then the gained midbody compound is reduced,
In the formula:
Formula
Figure 911012184_IMG13
Group, R 1, R 2, R 3, R 4, R 5And R 6Definition the same,
(iii) following formula: compound or its salt reduction:
In the formula:
Formula Group is ring (rudimentary) alkenyl,
R 1, R 2, R 3, R 4, R 5And R 6Definition the same,
Obtain following formula: compound or its salt:
Figure 911012184_IMG16
In the formula:
Formula
Figure 911012184_IMG17
Group is ring (rudimentary) alkyl,
R 1, R 2, R 3, R 4, R 5And R 6Definition the same,
(iv) following formula: compound and formula
Figure 911012184_IMG18
The compound or its salt reaction:
In the formula:
Formula Group is ring (rudimentary) alkyl or ring (rudimentary) alkenyl,
R 1, R 2, R 3, R 4, R 5Definition the same,
Obtain following formula: compound or its salt:
In the formula:
A group, R 1, R 2, R 3, R 4And R 5Definition the same,
(v) following formula: compound or its salt are carried out cancellation, the reaction of alcohol:
Figure 911012184_IMG22
In the formula:
Formula
Figure 911012184_IMG23
Group, R 1, R 2, R 3And R 4Definition the same,
Obtain down compound or its salt:
Figure 911012184_IMG24
In the formula:
Formula
Figure 911012184_IMG25
Group, R 1, R 2, R 3And R 4Definition the same,
(ⅵ) following formula: compound or its salt and formula R 7The compound reaction:
Figure 911012184_IMG26
In the formula;
Figure 911012184_IMG27
Group, R 1, R 2, R 5And R 6Definition the same,
R 7Be lower alkane ketone or lower alkanols alkanal, wherein have one or more suitable substituting groups separately; Rudimentary acetylenic ketone or rudimentary alkynes aldehyde wherein can have one or more suitable substituting groups separately; Perhaps can have one or more suitable substituent ring (rudimentary) alkane ketones;
With the reduction of gained midbody compound, obtain following formula: compound or its salt then;
Figure 911012184_IMG28
In the formula:
Formula
Figure 911012184_IMG29
Group, R 1, R 2, R 3, R 5And R 6Definition the same.
CN91101218A 1990-03-08 1991-03-07 New substituted amine compound and preparation method thereof Pending CN1054586A (en)

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GB909021806A GB9021806D0 (en) 1990-10-08 1990-10-08 A novel substituted-amine compound and a process for the preparation thereof

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CN110963877B (en) * 2019-12-18 2022-10-04 河北旭阳能源有限公司 Preparation method of 1-chloro-1-chloroacetyl cyclopropane

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